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IL-12 gene therapy protects mice in lethal Klebsiella pneumonia.

M J Greenberger, S L Kunkel, R M Strieter, N W Lukacs, J Bramson, J Gauldie, F L Graham, M Hitt, J M Danforth and T J Standiford
J Immunol October 1, 1996, 157 (7) 3006-3012;
M J Greenberger
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S L Kunkel
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R M Strieter
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N W Lukacs
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J Bramson
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J Gauldie
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F L Graham
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M Hitt
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J M Danforth
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T J Standiford
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Abstract

IL-12 is a proinflammatory cytokine that has recently been shown to have beneficial effects in the setting of acquired host immunity. To determine the role of IL-12 in innate immunity against Gram-negative bacterial organisms, CBA/J mice were challenged with 10(2) CFU of Klebsiella pneumoniae intratracheally (i.t.), resulting in the time-dependent expression of IL-12 mRNA (p35 and p40) and protein within the lung. Passive immunization of animals with anti-IL-12 serum i.p. at the time of K. pneumoniae inoculation resulted in a 12-fold increase in K. pneumoniae CFU in lung homogenates at 48 h, as compared with animals receiving control serum. In addition, treatment of Klebsiella-infected mice with anti-IL-12 Abs significantly decreased both short and long term survival. To assess the effect of compartmentalized IL-12 overexpression on outcome in Klebsiella pneumonia, animals were treated i.t. with 5 x 10(8) PFU of a nonreplicating adenoviral vector containing a human cytomegalovirus promoter and cDNAs coding for the p35 and p40 subunits of IL-12 inserted into the E1 and E3 domains (Ad5mIL-12), respectively. In vivo transfection with Ad5mIL-12 resulted in 45% long term survival in Klebsiella pneumonia, whereas no animals with Klebsiella pneumonia receiving control adenovirus survived. Moreover, treatment with anti-IFN-gamma Abs or soluble TNF receptor:Ig construct partially and completely attenuated survival benefits observed in animals receiving Ad5mIL-12, respectively. In conclusion, endogenous IL-12 is a critical component of antibacterial host defense, and the compartmentalized overexpression of IL-12 using recombinant adenoviral gene therapy represents a safe and effective approach to deliver IL-12 to the lung in the setting of murine Klebsiella pneumonia.

  • Copyright © 1996 by American Association of Immunologists

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The Journal of Immunology
Vol. 157, Issue 7
1 Oct 1996
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IL-12 gene therapy protects mice in lethal Klebsiella pneumonia.
M J Greenberger, S L Kunkel, R M Strieter, N W Lukacs, J Bramson, J Gauldie, F L Graham, M Hitt, J M Danforth, T J Standiford
The Journal of Immunology October 1, 1996, 157 (7) 3006-3012;

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IL-12 gene therapy protects mice in lethal Klebsiella pneumonia.
M J Greenberger, S L Kunkel, R M Strieter, N W Lukacs, J Bramson, J Gauldie, F L Graham, M Hitt, J M Danforth, T J Standiford
The Journal of Immunology October 1, 1996, 157 (7) 3006-3012;
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Print ISSN 0022-1767        Online ISSN 1550-6606